Generic name: doxycycline hyclate
Dosage form: tablet, capsule
Drug class: Tetracyclines
Indications and Usage for Acticlate
Acticlate® and Acticlate® CAP are indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox, and tick fevers caused by Rickettsiae.
Sexually Transmitted Infections
Acticlate and Acticlate CAP are indicated for treatment of the following sexually transmitted infections:
- Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis.
- Nongonococcal urethritis caused by Ureaplasma urealyticum.
- Lymphogranuloma venereum caused by Chlamydia trachomatis.
- Granuloma inguinale caused by Klebsiella granulomatis.
- Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
- Chancroid caused by Haemophilus ducreyi.
Respiratory Tract Infections
Acticlate and Acticlate CAP are indicated for treatment of the following respiratory tract infections:
- Respiratory tract infections caused by Mycoplasma pneumoniae.
- Psittacosis (ornithosis) caused by Chlamydophila psittaci.
- Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.
- Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:
- Respiratory tract infections caused by Haemophilus influenzae.
- Respiratory tract infections caused by Klebsiella species.
- Upper respiratory infections caused by Streptococcus pneumoniae.
Specific Bacterial Infections
Acticlate and Acticlate CAP are indicated for treatment of the following specific bacterial infections:
- Relapsing fever due to Borrelia recurrentis.
- Plague due to Yersinia pestis.
- Tularemia due to Francisella tularensis.
- Cholera caused by Vibrio cholerae.
- Campylobacter fetus infections caused by Campylobacter fetus.
- Brucellosis due to Brucella species (in conjunction with streptomycin).
- Bartonellosis due to Bartonella bacilliformis.
Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.
Acticlate and Acticlate CAP are indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:
- Escherichia coli
- Enterobacter aerogenes
- Shigella species
- Acinetobacter species
- Urinary tract infections caused by Klebsiella species.
Acticlate and Acticlate CAP are indicated for treatment of the following ophthalmic infections:
- Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.
- Inclusion conjunctivitis caused by Chlamydia trachomatis.
Anthrax Including Inhalational Anthrax (Post-Exposure)
Acticlate and Acticlate CAP are indicated for the treatment of Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure); to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
Alternative Treatment for Selected Infections when Penicillin is Contraindicated
Acticlate and Acticlate CAP are indicted as an alternative treatment for the following selected infections when penicillin is contraindicated:
- Syphilis caused by Treponema pallidum.
- Yaws caused by Treponema pallidum subspecies pertenue.
- Listeriosis due to Listeria monocytogenes.
- Vincent’s infection caused by Fusobacterium fusiforme.
- Actinomycosis caused by Actinomyces israelii.
- Infections caused by Clostridium species.
Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne
In acute intestinal amebiasis, Acticlate and Acticlate CAP may be a useful adjunct to amebicides.
In severe acne, Acticlate and Acticlate CAP may be useful adjunctive therapy.
Prophylaxis of Malaria
Acticlate and Acticlate CAP are indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see Dosage and Administration ( 2.4 ) and Patient Counseling Information ( 17 )].
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Acticlate and Acticlate CAP and other antibacterial drugs, Acticlate and Acticlate CAP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Acticlate Dosage and Administration
Important Administration Instructions
- The usual dosage and frequency of administration of Acticlate and Acticlate CAP differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of adverse reactions.
- Administer Acticlate and Acticlate CAP with adequate amounts of fluid to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions ( 6 )].
- If gastric irritation occurs, Acticlate and Acticlate CAP may be given with food or milk [see Clinical Pharmacology ( 12.3 )]
- Swallow Acticlate CAP whole. Do not break, open, crush, dissolve or chew the capsule.
- Acticlate tablets (150 mg) can be broken into two-thirds or one-third to provide a 100 mg and 50 mg strength, respectively [see FDA-approved patient labeling ].
Dosage in Adult Patients
- The usual dosage of Acticlate is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours.
- In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.
- For certain selected specific indications, the recommended duration or dosage and duration of Acticlate or Acticlate CAP in adult patients are as follows:
- Streptococcal infections, therapy should be continued for 10 days.
- Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis: 100 mg by mouth twice-a-day for 7 days.
- Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose.
- Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg by mouth twice-a-day for 7 days.
- Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks.
- Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks.
- Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg by mouth, twice-a-day for at least 10 days.
- Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days.
Dosage in Pediatric Patients
- For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of Acticlate and Acticlate CAP is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see Warnings and Precautions ( 5.1 )].
- For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of Acticlate and Acticlate CAP is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used.
Dosage for Prophylaxis of Malaria
For adults, the recommended dose of Acticlate is 100 mg daily.
For pediatric patients 8 years of age and older, the recommended dosage of Acticlate and Acticlate CAP is 2 mg per kg of body weight administered once daily. Pediatric patients weighing 45 kg or more should receive the adult dose.
Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.
Dosage for Inhalational Anthrax (Post-Exposure)
For adults, the recommended dosage is 100 mg, of Acticlate, by mouth, twice-a-day for 60 days.
For pediatric patients weighing less than 45 kg, the recommended dosage of Acticlate and Acticlate CAP is 2.2 mg per kg of body weight, by mouth, twice-a-day for 60 days. Pediatric patients weighing 45 kg or more should receive the adult dose.
Dosage Forms and Strengths
Acticlate (doxycycline hyclate) Tablets, 75 mg are round, convex, light-teal, film-coated, tablets with “75” debossed on one side of the tablet and “AQ101” debossed on the other (each tablet contains 75 mg doxycycline as 86.6 mg doxycycline hyclate).
Acticlate (doxycycline hyclate) Tablets, 150 mg are oval-shaped, convex, mossy-green, film-coated tablets. Each side of the functionally scored tablet has two parallel score lines for splitting into 3 equal portions with “A” debossed on each portion of one side of the tablet, and no debossing on the other (each tablet contains 150 mg doxycycline as 173.2 mg doxycycline hyclate).
Acticlate CAP Capsules:
Acticlate CAP (doxycycline hyclate) Capsules, 75 mg have a navy blue opaque body and cap with the inscription “AQUA 101C75” in black (each capsule contains 75 mg doxycycline as 86.6 mg doxycycline hyclate).
Acticlate and Acticlate CAP are contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.
Warnings and Precautions
The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use Acticlate and Acticlate CAP in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Acticlate and Acticlate CAP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.
Potential for Microbial Overgrowth
Acticlate and Acticlate CAP may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue use and institute appropriate therapy.
Severe Skin Reactions
Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline [See Adverse Reactions ( 6 )]. If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.
Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Acticlate and Acticlate CAP. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Acticlate and Acticlate CAP should be avoided because isotretinoin is also known to cause pseudotumor cerebri.
Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.
Delayed Skeletal Development
All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg per kg every six hours. This reaction was shown to be reversible when the drug was discontinued.
Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus.
The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.
Incomplete Suppression of Malaria
Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.
Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.
Development of Drug-Resistant Bacteria
Prescribing Acticlate and Acticlate CAP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Laboratory Monitoring for Long-Term Therapy
In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed.
The following adverse reactions have been identified during clinical trials or post-approval use of tetracycline-class drugs, including doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development [See Warnings and Precautions ( 5.1 )]. Instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration ( 2.1 )].
Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity has been reported [see Warnings and Precautions ( 5.3 )].
Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions ( 5.8 )].
Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS).
Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines [see Warnings and Precautions ( 5.6 )].
Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.
Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines, including Acticlate and Acticlate CAP in conjunction with penicillin.
Antacids and Iron Preparations
Absorption of tetracyclines, including Acticlate and Acticlate CAP is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations.
Concurrent use of tetracyclines, including Acticlate and Acticlate CAP may render oral contraceptives less effective.
Barbiturates and Anti-Epileptics
Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity.
Drug and Laboratory Test Interactions
False elevations of urinary catecholamines may occur due to interference with the fluorescence test.
USE IN SPECIFIC POPULATIONS
Teratogenic Effects. Pregnancy Category D: [see Warnings and Precautions ( 5.7 )]
There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1
A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2
A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3
Nonteratogenic effects: [see Warnings and Precautions ( 5.1 , 5.7 )].
Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown4. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions ( 5.1 , 5.7 )].
Because of the effects of drugs of the tetracycline-class on tooth development and growth, use Acticlate and Acticlate CAP in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies [see Warnings and Precautions ( 5.1 , 5.7 ) and Dosage and Administration ( 2.1 , 2.5 )].
Clinical studies of doxycycline hyclate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Acticlate Tablets each contains less than 1 mg of sodium.
In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.
Acticlate (doxycycline hyclate) Tablets and Acticlate CAP (doxycycline hyclate) Capsules contain doxycycline hyclate, a tetracycline class drug synthetically derived from oxytetracycline, in an immediate release formulation for oral administration.
The molecular formula of doxycycline hyclate is (C22H24N2O8 • HCl)2• C2H6O• H2O and the molecular weight of doxycycline hyclate is 1025.87. The chemical name for doxycycline hyclate is:
4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.
The structural formula for doxycycline hyclate is:
Figure 1: Structure of Doxycycline Hyclate
Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates.
Acticlate is available as 75 mg and 150 mg tablets. Each 75 mg tablet contains 86.6 mg of doxycycline hyclate equivalent to 75 mg of doxycycline. Each 150 mg tablet contains 173.2 mg of doxycycline hyclate equivalent to 150 mg of doxycycline.
Inactive ingredients in the tablet formulation are: microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium and magnesium stearate. Film-coating contains: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue #1 (75 mg Tablet), FD&C Blue #2 (150 mg Tablet) and yellow iron oxide (150 mg Tablet). Acticlate Tablets, 75 mg contain 0.34 mg (0.0146 mEq) of sodium. Acticlate Tablets, 150 mg contain 0.68 mg (0.0295 mEq) of sodium.
Acticlate CAP Capsule:
Acticlate CAP is available as 75 mg capsules. Each 75 mg capsule contains 86.6 mg of doxycycline hyclate equivalent to 75 mg of doxycycline.
Inactive ingredients in the capsule formulation are: microcrystalline cellulose, magnesium stearate, and a hard gelatin capsule which contains titanium dioxide, FD&C Red #40 and FD&C Blue #1. The capsules are printed with edible ink containing ammonium hydroxide, propylene glycol, isopropyl alcohol, N-butyl alcohol, black iron oxide, and shellac glaze in ethanol.
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